The liver is the only vital organ, aside from the brain, for which there is no pharmacological, mechanical, or extra corporeal means of support for a failing organ, such as are found for the lungs, kidney and heart. The liver is also unique in that it is the only mammalian organ that can regenerate its biologically functional parenchymal mass following resection or injury, instead of healing with biologically nonfunctional scar tissue.
Liver resections have become safer in the past 10 years, owing to improvements in preoperative diagnosis, surgical techniques and postoperative care. Postoperative mortality correlates directly with preoperative liver function and resected liver volume. Function of the remnant liver rapidly recovers in patients with normal liver parenchyma as hepatocytes proliferate to restore the loss of volume. However, in the presence of parenchymal liver disease, as in patients with liver cirrhosis, severe liver steatosis or colorectal liver metastasis, debilitated by neoadjuvant chemotherapy before liver resection, hepatocellular proliferation is impaired, exposing patients to liver dysfunction and associated complications, culminating in posthepatectomy liver failure, which has a high mortality (60-90%).
Several pathways have been identified in the regenerating liver including a cytokine pathway that is largely responsible for the entry of hepatocytes into the cell cycle (transition from G0 to G1), a process that is known as priming, and a growth factor pathway that is responsible for cell-cycle progression (G1 phase to the S phase).
In addition, ischemia-reperfusion injury of the liver is another known, clinically significant manifestation of surgical procedures, such as liver transplantation and partial hepatic resection (1). There are two distinct phases of liver injury after ischemia-reperfusion injury. The initial phase (<2 h after reperfusion) is characterized by oxidant stress, where production and release of reactive oxygen species (ROS) appears to directly result in hepatocelluar injury. The late phase (6-48 h after reperfusion) is an inflammatory disorder mediated by recruited neutrophils. Interrelationships between products of activated Kupffer cells and neutrophils, such as tumor necrosis factor (TNF-α), interleukin (IL)-1, nitric oxide (NO) and leukotrienes, have been implicated in the pathogenesis of hepatic ischemia-reperfusion injury (2). The biological effects of TNF-α extend from inducing cell death to promoting cell regeneration.
Indeed, recent studies have shown that ischemic preconditioning may be associated with entry of hepatocytes into the cell cycle within 2 h of subsequent ischemia-reperfusion in a murine model of partial hepatic IR injury (11).
Adenosine, through its binding to selective G-protein-associated membrane receptors, designated as A1, A2A, A2B and A3, accumulates extracellularly following ischemia, and is known to confer cytoprotection. In particular, the A3AR has been found to be involved in mediating cardio-neuro- and chemo-protection (3-7).
The A3 adenosine receptor, a Gi protein-associated cell surface receptor, has been proposed as a target to combat cancer and inflammation. The receptor is highly expressed in various tumor cell types while low expression was shown in adjacent normal tissues. In vivo studies have shown that A3AR agonists inhibit the development of colon, prostate and pancreatic carcinomas as well as melanoma and hepatoma.
A3AR agonists were also been shown to act as anti-inflammatory agents by ameliorating the inflammatory process in different experimental autoimmune models such as rheumatoid arthritis, Multiple sclerosis and Crohn's disease.
Moreover, A3AR agonists have been shown to possess a differential effect on tumor and normal cell growth. While activation of the A3AR inhibits the growth of various tumor cell lines, it stimulates the proliferation of normal cells such as bone marrow cells (8-10).
At present, there is no pharmacological intervention proven to either attenuate liver cell injury or to augment tissue regeneration of the liver after acute or chronic injury of this vital organ.